The NMDA receptor complex: a promising target for novel antiepileptic strategies.

Antiepileptic drugs (AEDs) cover a broad spectrum of pathological conditions ranging from seizures following congenital or acquired brain disorders to behavioural and psychiatric disorders and recently neuropathic pain. The need for novel antiepileptics raises from the expanding field of indications as well as from the fact, that special seizure types are refractory to common AEDs. In addition, many of the conventional antiepileptic drugs exhibit an unfavourable side-effect profile. Since there is growing evidence, that NMDA receptor activation might play a crucial role in epilepsy, NMDA receptor antagonists have become compounds of interest in preventing and treating seizures. This review focuses on NMDA receptor antagonistic compounds, which are already in use for the treatment of epileptic seizures (i. e. MgSO4, felbamate) and compounds in clinical trials (i. e. remacemide, ADCI). Further interest is put on NMDA antagonists in preclinical and biological testing (memantine, dizocilpine, conantokins, Co101244/PD174494, ifenprodil, arcaine, L-701,324, eliprodil, CGP40116, LY235959, LY233053, MRZ2/576, LU73068, 4-Cl-KYN). Some of the latter compounds are predominantely of academic interest (i. e. 4-Cl-KYN), others (i. e. dizocilpine, LY235959, LY233053) might be of therapeutical value when combined with conventional AEDs. In order to reduce adverse effects in antiepileptic medication using NMDA antagonists, special interest will be focused on subtype selective compounds. In this respect, Co101244, a novel potent and selective NR1/2B NMDA receptor antagonist might be a lead for therapeutically promising compounds.

A novel series of 2-carboxytetrahydroquinolines provides new insights into the eastern region of glycine site NMDA antagonists.

A series of potent 4-substituted tetrahydroquinolines has been synthesized and biologically tested in order to refine the eastern region of the pharmacophore model for glycine site NMDA antagonists concerning the assessment of lipophilicity, flexibility, and hydrogen bonding. Displacement studies on rat cortical membranes using [3H]-5,7-dichlorokynurenic acid as a radioligand indicated that binding affinities are markedly enhanced when additional hydrogen-accepting groups are introduced into the eastern region of the 2-carboxytetrahydroquinolines. Among the most potent ligands were some urea, sulfonylurea, and crown ether compounds as interesting leads for new diagnostics, especially for the evaluation of PET tracers, which allow biodistribution studies and NMDA receptor studies in the living organism.

Benzimidazoles as NMDA glycine-site antagonists: study on the structural requirements in 2-position of the ligand.

A series of different substituted benzimidazole derivatives has been synthesized and evaluated for the ability to displace [3H]MDL-105,519 to rat cortical membranes. Two benzimidazole-2-carboxylic acids 9 b and 9 c, in this substitution pattern not yet described as glycine antagonists, showed IC50 values of 0.89 microM (9 b) and 38.0 microM (9 c). Replacement of the carboxylate function in 2-position by a sulfonic acid moiety appreciably increased solubility, but decreased the affinity giving evidence for the strong need of the carboxylate group within the ligand. Further structure-activity studies using benzimidazole-2-one derivatives with an acetic acid moiety adjacent to a ring nitrogen revealed new insights into the importance of amide functionalities within the heterocycle for the affinity of antagonist glycine-site ligands.

The glycine site on the NMDA receptor: structure-activity relationships and possible therapeutic applications.

L-glutamate is the most important fast excitatory neurotransmitter in the mammalian central nervous system. Glutamate receptors are classified into two main categories: ionotropic and metabotropic. The N-methyl-D-aspartate (NMDA) receptor, which is associated with an ion channel, seems to play an important role in glutamate excitotoxicity, a process thought to be involved in a number of neurodegenerative disorders such as focal cerebral ischaemia (stroke), Parkinsonís, Huntingtonís, Alzheimerís disease, schizophrenia and epilepsy. The unique glycine site on the NMDA receptor, discovered by Johnson and Ascher in 1987, represents an interesting target for the development of neuroprotective compounds. Glycine antagonists may offer advantages over other NMDA antagonists in terms of their side-effect profile, especially in the long-term treatment of chronical neurodegenerative disorders but also in the treatment of serious medical emergencies with a significant morbidity and mortality like status epilepticus or stroke. So far it is not clear whether NMDA receptor antagonists including glycine antagonists would be suitable for chronic administration because of their effects on cognition, learning and motor function. High-affinity, in vivo potent, glycine antagonists of great structural diversity (i. e. pyrido[2,3-b]pyrazine-N-oxides, indole-2-carboxylates, 4-substituted-3-phenylquinoline-2(1H)-ones and alkyl-substituted 1,4-dihydro-quinoxaline-2,3-diones) are now available and their suitability for long-term treatment of chronical neurodegenerative disorders has to be investigated in clinical trials.